Use of 2,4 - diamino - 6 - substituted - s - triazines for inducing depressant effects in animals



United States Patent USE OF 2,4 DIAMINO 6 SUBSTITUTED s TRI- AZINES FOR INDUCING DEPRESSANT EFFECTS IN ANIMALS James R. Albert and Jim K. Kodama, Modesto, Califi, assignors to Shell Oil Company, New York, N.Y., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 498,116, Oct. 19, 1965. This application Apr. 17, 1968, Ser. No. 721,925

Int. Cl. A61k 27/00 US. Cl. 424-249 Claims ABSTRACT OF THE DISCLOSURE Use of 2,4-diamino-6-substituted-s-triazines for inducing depressant efiects in animals.

This application is a continuation-in-part of copending application Ser. No. 498,116, filed Oct. 19, 1965 and now abandoned.

BACKGROUND OF THE INVENTION This invention relates to a method of inducing depressant effects in animals using certain s-triazines. More particularly it relates to the use of certain s-triazines as analgesics, muscle relaxants, anticonvulsants and tranquilizers and to pharmaceutical and veterinary compositions containing such triazines.

A considerable number of naturally occurring alkaloids and synthetic chemicals are available as useful analgesics, anticonvulsants and muscle relaxants. Repeated administration of many such analgesics creates the potential danger of drug addiction. The need for effective analgesics which minimize the hazards of drug addiction has long been recognized.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel method for inducing depressant eifects in mammals. These depressant effects include sedative, analgesic, muscle relaxant, anticonvulsant and tranquilizing elfects. Another object of the invention is to provide a novel method of pain control with minimum hazard of drug addiction. Yet another object is to provide a novel method for inducing depressant effects in mammals with certain 2,4-diamino-6-substituted-s-triazines. The provisions for supplying the art with novel pharmaceutical and veterinary compositions capable of inducing neurological depressant effects in mammals forms another object.

These and other objects are accomplished by administering to a mammal an effective dosage of a 2,4-diamino-6-substituted-s-triazine of the formula ITIRRI C wherein:

R is alkyl of l-S carbon atoms or phenyl and R is hydrogen or alkyl or 1-5 carbon atoms;

R is alkyl of 1-5 carbon atoms or hydrogen and R is alkyl of 1-5 carbon atoms, phenyl or chlorophenyl;

and

3,549,760 Patented Dec. 22, 1970 "ice where Q is trichloroacetic acid or 2,4,6-trichlorophenol and m is 0 or 1;

O 0R4 P where R is alkyl of 14 carbon atoms;

i-o-a1k 1 where alkyl is of l-3 carbon atoms;

ds-a1k 1 where alkyl is of 1-3 carbon atoms;

NHN=R where R is benzylidene or R OH CH=( J-GHa where R is alkyl of 1-3 carbon atoms; -NH-NHR7 where R7 is hydrogen,

0H s )HO C13, phenylcarbonyl or where R; is alkyl of 1-4 carbon atoms; -SR where R is cyanoalkyl of up to 4 carbon atoms or alkylthio of 13 carbon atoms;

ino N=NNCN where R is alkyl of 1-3 carbon atoms;

float NHz --C=NO-Rn where R is hydrogen or alkyl or 1-3 carbon atoms;

ONO

Where alkyl is of 1-3 carbon atoms; or --Cl.

Representative species of the above s-triazines are:

(12) 2-methylamino-4-(1,1-dimethylpropyl)amino-6- azido-s-triazine (13 2-propylamino-4-ethylamino-6-azido-s-triazine (l4) 2-methylamino-4-propylamino-6-azido-s-triazine (15 2,4-bis- (diethylarnino -6-diethoxyphosphinyl-striazine (16) 2-isopropylamino-4-ethylamino-6-diethoxyphosphinyl-s-triazine 17) 2,4-bis- (isopropylamino -6-methoxycarbonyl-striazine (18) 2-isopropylamino-4-methylamino-6-ethylthio thiocarbonyl -s-triazine (19) 2-ethylamino-4-isopropylamino-6- S-chloromethyl-1,2,4-oxadiazol-3-yl)-s-triazine (20) 2,4-bis- (isopropylamino -6-benzylidenehydrazino-s-triazine (21) 2,4-bisethylamino -6- 3 -hydroxy-1-methylbut-2-enylidene hydrazino-s-triazine (22) 2-anilino-4-dimethylamino-6hydrazino-s-triazine (23 2-ethylamino-4-isopropylamino-6-hydrazino-striazine (24) 2,4-bis- (dimethylamino -6- [2- 2,2,2-trichloro- 1-hydroxyethyl)hydrazino] -s-triazine 25) 2,4-bisisopropylamino -6- 2- 2,2,2-trichlorol hydroxyethyl hydrazino] -s-triazine 26) 2,4-bisethylamino) -6- 2-benzoylhydrazino -striazine 27) 2,4-bisdimethylamino -6- 2-dimethoxythiophosphinyl- 1 -hydrazino -s-triazine 28) 2,4-bis- (ethylamino) -6-( l-cyanopropylthio -s-triazine 29) 2-diethylamino-4-ethylamino-6-methyldithio-striazine (30) 2-ethylamino-4-tert-butylamino-6- 3-cyano-3-methyll-triazeno -s-triazine (31) 2,4bisethylamino -6- 5 -methyl-2-thiazolyl -striazine (32) 2-isopropylamino-4-propylamino-6-( l-amino- 1 -hydroxyiminomethyl -s-triazine (3 3) 2,4-bisisopropylamino -6-( l-aminol -ethoxyiminomethyl -trans-s-triazine (34) 2,4-bisisopropylamino -6-( l-amino- 1 -ethoxyiminomethyl -cis-s-triazine 35) 2,4-bisisopropylamino -6-( l-benzoyl- 1 -cyanolethoxycarbonylmethyl -s-triazine (3 6) 2-tert-butylamino-4-ethylamino-6-chloro-s-triazine Compositions according to the present invention also comprise a pharmaceutical carrier which may either be solid material or a liquid. Preparations for oral administration can be liquids or solids or any combination of these forms, such as syrups, elixirs, powders, capsules, or tablets. Preparations for administration of the active agent in unit dose form can be powders, compressed tablets, or a powder enclosed in a suitable capsule of absorbable material such as gelatin. The powders or compressed tablets may also comprise suitable excipients and/or diluents such as starch, lactose, stearic acid, magnesium stearate, dextrin or polyvinylpyrrolidone.

Preparations for topical application may be in the form of a liquid, a powder, a salve, or as a aerosol.

Preparations for parenteral administration may be sterile solutions or suspensions in liquids such as water, physiological saline, benzyl alcohol, ethyl oleate, methylcellulose, dimethyl sulfoxide or other liquid excipients known in the pharmaceutical and veterinary formulation art.

Any of the above preparations may contain the triazines of the invention or may contain in addition other pharmaceutically active agents. For example, for topical application it may be desirable to include a germicide and/or a fungicide.

The unit dosage or therapeutically effective quantity of the triazines used according to this invention as analgesics, m scle relaxants, anticonvulsants and/or tranquilizers can vary over wide limits. For oral or parenteral administration in some cases, as little as 0.01 miligram of the active material per kilogram of body weight can be effective in the reduction of pain or in effecting sedation and muscle relaxation, while seldom will a dosage in excess of about 500 milligrams per kilogram of body weight be required. In general, for oral administration, the effective dosage will be from about 1.0 to 200 milligrams per kilogram of body weight, while for parenteral administration, the effective dosage will be from about 0.10 to about 100 milligrams per kilograms of body weight. Each dosage unit form-each capsule, tablet, ampoule, or prescribed dose-can contain from about 1 percent to about percent of active material, based upon the total weight of the formulation and preferably contains from about 2.5 percent to about 50 percent of the active material, on the same basis. Of course, it is possible to administer the therapeutics without the use of a pharmaceutical carrier.

The therapeutic agents used according to the invention can be administered either prior to or after the onset of the condition to be treated, such as when they are used as: analgesics for the amelioration of pain; motor depressants or tranquilizers to relieve nervous tension; central depressants to reduce hyperexcitability and induce sedation; or as mucle relaxants for relief from pain and discomfort of disorders involving mucle spasms.

PREPARATION The s-triazines of this invention may be prepared by conventional methods known in the art for preparing these types of triazines. The following description is illustrative of some of the methods of preparation.

The starting materials for the s-triazines of this invention are cyanuric chloride or 2,4,6-tris-(trichloromethyl)- s-triazine. By successive replacement of the chloro or trichloromethyl groups of these compounds, the groups depicted in Formula I are introduced.

Thus, the amino groups, NRR NR R and piperazino, may be introduced by the conventional methods known in the art, e.g., as described by Elderfield, R. C., Heterocyclic Compounds, N.Y., John Wiley and Sons, 1961, vol. 7, pp. 66967l.

The cyano group may also be introduced by known methods, e.g., by reaction of a chloro-s-triazine with sodium cyanide in the presence of base such as trimethylamine. It is preferred that the sodium cyanide be added as an aqueous solution to a dioxane solution of the triazine. The method described in U.S. 3,234,225 may also be used.

The cyanato group (OCN) may be introduced by reaction of a hydroxy-s-triazine with cyanogen chloride in an ether solvent in the presence of a base such as triethylamine.

The aminooxy group (ONH may be introduced by the method described in German Pat. 1,232,588 while the thiocyanato group (SCN) may be introduced by the methods described in U.S. 3,120,468.

The aminothio group (SNH is introduced by reaction of a mercapto-s-triazine with sulfuryl chloride in a halogenated hydrocarbon diluent, followed by reaction with ammonia gas.

The azido group may be introduced by the methods described in U.S. 3,328,400 while the trichloroacetic acid and 2,4,6-trichlorophenol adducts of these azido-s-triazines are readily prepared by mixing the azido-s-triazine with trichloroacetic acid or 2,4,6-trichlorophenol in equimolar amounts.

The dialkoxyphosphinyl groups (PO(OR may be introduced by reaction of a chloro-s-triazine with a dialkyl ester of phosphoric acid in an aromatic solvent in the presence of sodium.

The alkoxycarbonyl group may be introduced by hydrolysis of a cyano-s-triazine with sodium hydroxide followed by alkylation with an appropriate dialkyl sulfate.

The C(S)S-alkyl group may be introduced by reaction of a trichloromethyl-s-triazine with NaSH in dimethylformamide followed by reaction with an alkyl bromide.

The S-chloromethyl-1,2,4-oxadiazol-3-yl group may be introduced by refluxing a mixture of a triazinyl carboxamide oxime and chloroacetyl chloride in benzene. The triazinyl carboxamide oxime may be prepared by refluxing a mixture of a cyano-s-triazine and hydroxylamine hydrochloride in an aqueous alcoholic solution of sodium hydroxide.

The first member of the -NHNHR- group, the hydrazino group, may conveniently be introduced by refluxing a mixture of a chloro-s-triazine and hydrazine hy- The following examples are illustrative of the preparation of some of the s-triazine of this invention.

EXAMPLE I 18.3 g. 2,4-bis-dimethylamino-fi-hydroxy-s-triazine and 7 g. cyanogen chloride were added to 100 ml. tetrahydrofuran and the mixture cooled to C. After adding 10.6 g. triethylamine, the mixture was stirred for 1 hour at room temperature and then evaporated under vacuum. The residue was taken up with water and methylene chloride. After distilling ofl? the solvents there was obtained 18.1 g. of the colorless oil, 2,4-bis-dimethylamino-G-cyanato-s-triazine.

drate in a lower alkanol diluent. The remaining members EXAMPLE H of h PP are P p y reacting the e To a stirred solution of 72 g. of (2,4-bis-(isopropylamitriaZlIlei Wlth chloral 7 is a) Wlth no)-6-trimethylammonium-s-triazinyl)-chloride in 50 ml. y ehloride 111 the P e triethylahilhe 7 is of water, was added 32.5 g. of sodium azide at room temp y y and W1th a dlallfoxy thlophosphofyl perature. The crystalline precipitate which formed, was Chloride in the Presence of trrethylamlne allower to stand for 1 hour. After filtering, Washing and (R7 is P(S) (OR8)2) dIyingiVISI 9g4. 905f 2,4-bis-(iiopropglamino)-6-azido-s-tri- The NHN=R group may be introduced (R is azme c"was 0 tame benzylidene) by reaction of a hydraZino-s-triazine with PREFERRED EMBODIMENTS benzaldehyde. The remaining members may be introduced by reacting an appropriate 1,3-diketone While the s-triazines of Formula I show some depressant effects in mammals, there are differences both quan- (R6 C(O)CH2C(O)CH3) titative and qualitative exhibited by individual members Wlth ahydfaziho's" trlaziheof the class. Especially preferred depressants because of The first member of the 9 group, 9 is y their activitiy as analgesics, muscle relaxants, anticonculy y be introduced y reacting a p sants, and/or tranquilizers are the s-triazines of Formula azine with a chloroalkyl cyanide in an aqueous solution I wherein R and R2 which may be the Same or diff nt of sodium hydroxide and acetone at moderate temperaare alkyl of 1-5 carbon atoms, R and R which may be tures- The other member of this group, 9 is alkylthiofi the same or diiferent, are hydrogen or alkyl of l-S carmay be introduced by reacting a mercapto-s-triazine with b t a d X i OCN or N --(Q) where Q is a compound of the formula y s in an aqueous trichloroacetic acid or 2,4,6-trichlorophenol and m is solution of sodium hydroxide. 0 or 1 The 1o) group y be introduced y Preferred s-triazines within this subclass are: refluxing a mixture of an azido-s-triazine and sodium cyanide in a lower alkanol, cooling the mixture and adding 40 2,4-bis-(dimethylamino)-6-cyanato-s-triazine an appropriate dialkyl sulfate. Z-tert-butylamino-4-ethylamino-6-azideo-s-triazine, tri- The 5-methyl-2-thiazolyl group may be introduced by chloroacetic acid adduct refluxing a mixture of a thiocarbamoyl-s-triazine, isopro- 2-isopropylamino-4-ethylamino-6-azido-s triazine, tripyl alcohol and chloroacetone. chloroacetic acid adduct The C(NH =NO-R group (R is hydrogen) 2-isopropylamino-4-ethylamino-6-azido-s-triazine, 2,4,6- may be introduced by refluxing a cyano-s-triazine with trichlorophenol adduct hydroxylamine hydrochloride in an aqueous alcoholic 2-methylamino-4-(1,l-dimethylpropyl)amino-6-azido-ssolution of sodium hydroxide. Reaction of a cyano-s-tritriazine azine with an O-alkyl hydroxylamine (H NOR in a 2-pr0pylamino-4-ethylamino-6-azido-s-triazine lower alkanol solvent in the presence of hydrogen sulfide Z-methylamino-4-propylamino-6-azido-s-triazine introduces the remaining members of this group.

The The following examples are presented to illustrate certain pharmacological responses induced by triazine com- O(CN) C(O) pheny1) (C(O)O'a1ky1 positions of the invention. These examples should in no group may be introduced by reacting a trimethylammo- Way be regarded as limiting the scope of the invention. nium-s-triazine with an alkyl ester of benzoylcyanoacetic The results of the various pharmacological responses acid in an aqueous solution of sodium hydroxide. tested are shown in Table I.

TABLE I Muscle relaxant, Anticonvulsant response (e) tranquilization response ((1) Maximal elec- Analgesie re- Pernicious tro-shock seiz- Antistrychnine Approximate Approximate sponseintraper- Muscle relaxpreening antagure antagonism response ratio analgesic dose, muscle relaxitoneal (c) analant rating at onism based on based on EDS" based on ED oral (a), ant dose, oral gesic rating at 10 mg./ kg. EDso 1.p. or 32 i.p. or 1.p. or mg./ kg. Test compound 1 mgJkg. (b), mg./kg. 100 mg./kg. 1.p. Ing./kg.1.p. mg./kg. 1.p. 1.p

TABLE I-Oontinued Muscle relaxant, Autieonvulsant response tranquilization response ((1) Maximal elec- Analgesic re- Pernicious tro-shock seiz- Antistrychnine Approximate Approximate spouse intraper- Muscle relaxpreening antagurc antagonism response ratio analgesic dose, muscle relaxitoneal (c), analant rating at onism based on based on ED50 based on EDsu oral (a), ant dose, oral gesio rating at rug/kg. ED50 i.p. or 32 i.p. or 100 i.p. or 180 mg./ kg. Test compound 1 mg./kg. (b), mg./kg. 100 mgJkg. i.p. mgJkg. i.p. nag/kg. i.p. 1.p.

1 Numbers correspond to numbered triazines in eols. 2 and 3.

Analgesic response (a) The presence of an analgesic effect was identified as an absence of a struggling or phonating response to a manual pinch of the tail of treated mice. The laboratory white mice for each treatment were placed in individual compartments. The mice were orally intubated with the test compound at the dosage of 500 milligrams per kilogram, and minutes, 1 hour, 2 hours, 4 hours and 24 hours after treatment a pinch of the tail was applied to each mouse. Any compound inducing an analgesic response in 50 percent of the mice at any of these test intervals was considered active in this test. Some of the compounds were tested at lower dosages.

While the exact safety factor has not been evaluated for all compounds of the invention, it has been found that the effective analgesic dose of the triazines of the invention is considerably lower than the toxic dose (LD Muscle relaxant response (b) As in (a) mice were orally intubated with the test compound and the muscle relaxant effects of the compounds were evaluated. The procedure for assessing skeletal muscle relaxant activity involves an evaluation of passivity, flaccidity and pinnal reflex blockage. Passivity is defined as an absence of the struggle behavior of the animal when manipulated manually and may indicate skeletal muscle relaxation, central depression, tranquilization, paralysis, or anesthesia. Flaccidity is measured by the decreased tonus of skeletal musclature and may indicate myorelaxant activity, central depression, or paralysis. The pinnal reflex is tested by touching the inner aspects of the ear with a fine wire to elicit a characteristic ear twitch. An impairment of this reflex suggests an inhibition of polysynaptic reflexes.

Analgesic responselntraperitoneal (c) The analgesic response was determined in laboratory white mice by injection of the triazines under test at an intraperitoneal dosage of 100' mg. per kg. The results were obtained by evaluation similar to that described for the Approximate Analgesic Dose0ral. The compounds were rated on a one plus to four plus scale. When 12 mice out of ten showed an analgesic response, a rating was assigned; indicated that 3-6 out of ten mice responded; indicated that 7-9 out of ten responded; while a rating meant that all ten mice gave an analgesic response at the dosage tested.

Muscle relaxant-Tranquilization response ((1) The muscle relaxant effects, as expressed by passivity, flaccidity and pinnal reflex blockage, were assessed in laboratory mice injected intraperitoneally with mg./ kg. of the test compound as in (b). In addition the tranquilizing effects of the compounds under test were evaluated by the pernicious preening test (Wilfon, J. G. et al. Fed. Proc. 19:20, 1960). The pernicious preening behavior was elicited by painting the rear of the mice with a pilocohesive dye. A violent unremitting tearing of the stiff, cohering strands of hair constitutes the pernicious preening behavior. Thirty minutes after injection, the pilocohesive dye was applied and the presence or absence of the compulsive behavior was noted for a 10 minute interval. The ratings for the muscle relaxant response are based upon the scale given in (0). Effective antagonism of pernicious preening is shown with the same scale as in (c). That is, +=1.2 mice out of ten, ++=36 mice out of ten, +++=7-9 mice out of ten and ++++=10 mice out of ten responded. Some of these values for the individual triazines were determined at a dosage of 32 mg./kg. while the others were determined on the basis of ED values, the dose at which 50 percent of the treated animals exhibit an effective response. These ED values were then translated into the 1+ to 4+ scale by the following criteria: ED values of 30-100 mg/kg=+, 10-30 mg./kg.=++, 3-10 mg./kg.=-|++ and 3 Anticonvulsant response (e) The test procedures used were maximal electroshock and antistrychnine assay methods. The test compound was intraperitoneally injected into laboratory mice and after 30 minutes the anticonvulsant activity was measured. The technique employed in the maximal electroshock method was essentially that of Swinyard, E. A., J. Amer. Pharm. Assoc. 38:201 (1949). The mice were subjected to an alternating current stimulus, about equal to three times the current necessary to produce maximal seizures, and prevention of the hindlimb tonic extensor phase was considered to be an effective anti-convulsant action. In the antistrychnine assay, the mice were intraperitoneally injected with the test compound and then were challenged with a lethal intraperitoneal dose of strychnine sulfate. Increase in survival time against the lethal action of strychnine of greater than three standard deviations of the control mean was considered an effective action. Anti-convulsant activity in these tests suggests skeletal muscle relaxation or efficacy against epileptic seizures. Effective antagonism of maximal electroshock seizure and antistrychnine activity are given on the same 1+ to 4+ scale as in (c). Some of these values for the individual triazines in the maximal electroshock seizure test were determined at a dosage of 100 mg./ kg. while the others were determined on the basis of ED values, the dose at which 50 percent of the treated animals exhibited an effective response. These ED values were then translated into the 1+ to 4+ scale by the following criteria: ED values of 100-300 mg./kg.=+, 30-100 mg./kg.=++, -30 mg./ kg.=++-+ and 10 mg./kg.=+;++. The antistrychnine activities for the individual triazines were also determined in either of two ways. Some are based on the response ratio at 180 mg./ kg. while the others on the ED values. The criteria for translating the ED values to the 1+ to 4+ scale is the same as for the maximal electroshock seizure test.

We claim as our invention:

1. A depressant veterinary and pharmaceutical composition comprising a (a) compound of the formula:

NRR

wherein R is alkyl of 1-5 carbon atoms or phenyl and R is hydrogen or alkyl of 1-5 carbon atoms;

R is alkyl of 1-5 carbon atoms or hydrogen and R is alkyl of 1-5 carbon atoms, phenyl or chlorophenyl;

and

-CN; -OCN; -H; ONH SCN; -SNH --N -(Q) where Q is trichloroacetic acid or 2,4,6- trichlorophenol and m is 0 or 1;

where R; is alkyl of 1-4 carbon atoms;

-('i-o-a1k 1 where alkyl is of 1-3 carbon atoms;

ORE

where R is alkyl of 1-4 carbon atoms; -R where R is cyanoalkyl of up to 4 carbon atoms or alkylthio of 1-3 carbon atoms;

where R is alkyl of 1-3 carbon atoms; where R is hydrogen or alkyl of 1-3 carbon atoms Where alkyl is of l-3 carbon atoms; or -Cl; and (b) a physiologically acceptable carrier, the percent by weight of (a) in the total formulation being from about one to about 95.

2. The veterinary and pharmaceutical composition of claim 1 wherein R and R which may be the same or different, are alkyl of 1-5 carbon atoms, R and R;,, which may be the same or difierent, are hydrogen or alkyl of 1-5 carbon atoms, and X is OCN or -N (Q) m where Q is trichloroacetic acid or 2,4,6-trichlorophenol and m is 0 or 1.

3. The veterinary and pharmaceutical composition of claim 2 wherein R is methyl, R is isopropyl, R and R are both hydrogen and X is N;;.

4. The veterinary and pharmaceutical composition of claim 2 wherein R, R R and R are methyl is now. -OCN.

5. A method of inducing a depressant response in mammal comprising administering to said mammal in need thereof an effective dosage of a compound of the formula:

wherein R is alkyl of 1-5 carbon atoms or phenyl and R is hydrogen or alkyl of 1-5 carbon atoms;

R is alkyl of 1-5 carbon atoms or hydrogen and R is alkyl of 1-5 carbon atoms, phenyl or chlorophenyl;

and

-OCN; H; -ONH -SCN SNH N '(Q) where Q is trichloroacetic acid or 2,4,6- trichlorophenol and m is 0 or 1;

where R is alkyl of 1-4 carbon atoms;

0 I*O-alkyl Where alkyl is of 1-3 carbon atoms;

0 3-o-a1k 1 where alkyl is of 1-3 carbon atoms;

NHN=R where R is benzylidene or Rs OH =CH=( JCHa where R is alkyl of 1-3 carbon atoms; NH-NHR where R is hydrogen,

OH 3HG C13 S ORB 1 1 where R; is alkyl of 14 carbon atoms; SR where R is cyanoalkyl of up to 4 carbon atoms or alkylthio where R is alkyl of 13 carbon atoms;

Zlfjom where alkyl is of 1-3 carbon atoms; or Cl.

6. The method of claim 5 wherein said compound is administered orally to said mammal.

7. The method of claim 5 wherein said compound is administered parenterally to said mammal.

8. The method of claim 5 wherein R and R which may be the same or different, are alkyl of 1-5 carbon atoms, R and R which may be the same or different, are hydrogen or alkyl of l-S carbon atoms, and X is CN or N -(Q) where Q is trichloroacetic acid or 2,4,6-trichlorophenol and m is 0 or 1.

9. The method of claim 8 wherein R is methyl, R is isopropyl, R and R are both hydrogen and X is N 10. The method of claim 8 wherein R, R R and R are methyl and X is OCN.

References Cited UNITED STATES PATENTS 2,867,621 1/1959 Grundmann 260249.5

FOREIGN PATENTS 1,329,306 4/1963 France 260249.5

ALBERT T. MEYERS, Primary Examiner D. M. STEPHENS, Assistant Examiner US. Cl. X.R. 424200 

